Background
The glycerol-3-phosphate dehydrogenase 1 (
GPD1; MIM 138420) gene, which is mapped to chromosome 12q12-q13, encodes cytoplasmic NAD-dependent GPD1 that is crucial in both carbohydrate and lipid metabolism by catalyzing the reversible redox reaction of dihydroxyacetone phosphate (DHAP) and reduced nicotine adenine dinucleotide (NADH) to glycerol-3-phosphate (G3P) and NAD
+ [
1,
2]. Under physiological conditions, the reaction strongly favors the formation of G3P [
2]. Glycerol-3-phosphate dehydrogenase 2 (
GPD2; MIM 138430) is located on the outer surface of the inner mitochondrial membrane and catalyzes the unidirectional reaction of G3P and flavin adenine dinucleotide (FAD) to DHAP and FADH
2 [
2]. Together with a mitochondrial GPD2, GPD1 forms the G3P shuttle mainly in the brain and skeletal muscle of mammals, which transfers reducing equivalents from the cytosol to the mitochondria [
3]. The human GPD1 is organized into two distinct domains, the
N-terminal eight-stranded β-sheet sandwich domain (from residues 3–190) and the
C-terminal helical substrate-binding (from residues 193–349) domain [
2]. NAD
+ binds to GPD1 at the periphery of its β-sheet core (10-GSGNWG-15) [
2].
GPD1 mutations were first identified by Basel-Vanagaite
et al. as the cause of transient infantile hypertriglyceridemia (HTGTI; OMIM 614480) in 10 individuals from four consanguineous Israeli Arab families carrying a homozygous founder mutation c.361-1G>C [
3]. HTGTI manifests as early onset hepatomegaly, hypertriglyceridemia, moderately elevated transaminases, hepatic steatosis, and hepatic fibrosis [
3]. Recently, Li
et al. reported biallelic mutations in
GPD1 gene of a Chinese boy who presented with a different phenotype comprising obesity, insulin resistance, fatty liver, and short stature [
4]. To date, only four reports have described 16 patients harboring homozygous or compound heterozygous mutations in the
GPD1 gene [
3‐
6]. Here, we describe a
Han Chinese patient with a novel
GPD1 homozygous mutation who presented with hepatomegaly, elevated transaminases, hypertriglyceridemia, and fatty liver in infancy.
Discussion and conclusions
HTGTI is a rare autosomal recessive disorder that has been described in a total of 15 affected individuals in three studies [
3,
5,
6]. The shared features of these patients include infantile hypertriglyceridemia, elevated liver enzymes, hepatomegaly, liver steatosis and fibrosis. Additional uncommon phenotypes include fasting hypoglycemia and kidney disease. We report the first
Han Chinese patient with HTGTI, and the patient carried a novel homozygous nonsense mutation in the
GPD1 gene, which is the causative variation. Our patient clinically resembled other reported children with HTGTI: She presented with elevated liver transaminases, hypertriglyceridemia, marked hepatomegaly, and hepatic steatosis since early infancy. Electron microscopy was only undertaken in one of 15 previous affected patients, revealing interhepatocytic, not intrahepatocytic, vesicles (most likely fat) [
6]. By contrast, electron microscopy showed intrahepatocytic, not interhepatocytic, lipid droplets in our patient; however, the significance of this difference is unclear. Although our patient was not given treatment since 6.5 months old, the levels of triglyceride and liver enzymes decreased at the last evaluation at the age of 1 year and 3 months. The heterozygote (carrier) parents and older brother of our reported patient were asymptomatic. The mildly elevated liver functions of the father may be due to his high body mass index.
Recently, Li
et al. reported biallelic mutations (c.220-2A>G and c.820G>A) in
GPD1 gene of a 13-year, 8-month-old Chinese boy who presented with obesity, insulin resistance, fatty liver, dermal abnormalities (facial acne, acanthosis nigricans, and hirsutism), short stature, elevated dehydroepiandrosterone sulfate and lipoprotein-α levels, which were different from HTGTI phenotype [
4]. Clinical features and molecular genetics of individuals with biallelic mutations in
GPD1 gene were shown in Table
2. Li
et al. also suggested that the
GPD1 gene should be considered as the short stature causing gene [
4]. However, it is uncertain that the different phenotype of the adolescent patient was due to phenotypic heterogeneity or having an unrecognized second disorder.
Table 2
Clinical features and molecular genetics of individuals with biallelic mutations in GPD1 gene
Patient | F1-IV1 | F1-IV2 | F1-IV4 | F2-II6 | F2-III1 | F3-V1 | F3-V2 | F3-V3 | F4-II4 | F4-III3 | 11 | A | B | C | D | 16 | 17 |
Gender | M | M | M | M | F | F | F | F | M | M | F | M | F | M | M | M | F |
Descent | Israeli Arab | Caucasian | Arab-Muslim | NA | Italian | Italian | Chinese | Chinese |
Consanguinity | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | NA | Yes | No | Yes | NA | No | No |
Term birth | NA | NA | No | NA | Yes | Yes | Yes | Yes | No | No | Yes | NA | Yes | Yes | NA | Yes | Yes |
Birth weight (g) | 3,000 | NA | 2,180 | 3,395 | 2,570 | 3,000 | 2,430 | 2,190 | 1,950 | 2,160 | NA | NA | 3,500 | 3,640 | NA | 2900 | 3,150 |
Presenting age (m) | 1 | 1 | 4–6 | Birth | 6 | 2.5 | 7 | 7 | 9 | 3.5 | Birth | 10 | 12 | 5 | 24 | 84 | 3.5 |
Age at last test (y) | 13.7 | 9.9 | 11.9 | 23 | 2.9 | 4.3 | 1.3 | 1.3 | 12.5 | 12.5 | 1.5 | 4.5 | 4 | 7 | 31 | NA | 1.2 |
Initial TG (mg/dl) | 6244 | 250 | 990 | 520 | 1208 | 349 | 258 | 330 | 225 | 566 | 839 | 170 | 1180 | 466 | 213 | N | 388 |
Last TG (mg/dl) | 250 | 247 | 289 | 170 | 202 | 135 | 185 | 202 | 301 | 434 | 536 | N | N | 271 | NA | NA | 370 |
TGa(mg/dl) | 10–150 | 50-130 | 40-150 | NA | 50-150 |
Initial CH (mg/dl) | 420 | 109 | 164 | 101 | 109 | 66 | 95 | 99 | 106 | 149 | 197 | 155 | 260 | N | NA | N | 95 |
Last CH (mg/dl) | 73 | 207 | 172 | 114 | 184 | 202 | 118 | 141 | 188 | 256 | NA | NA | NA | NN | 204 | NA | 168 |
CHa (mg/dl) | <170 | <170 | 120-200 | NA | 120-201 |
Elevated transaminases | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
Hepatomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
Splenomegaly | NA | NA | No | Yes | NA | No | Yes | Yes | No | No | NA | No | No | Yes | NA | No | No |
Hepatic steatosis | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Short stature | No | No | Yes | Yes | No | No | No | No | Yes | Yes | No | NA | NA | No | NA | Yes | No |
Other findings | No | No | No | No | No | No | No | No | Horseshoe kidney; Transient hypotonia | Craniocerebral involvement | No | Fasting hypoglycemia | No | Kidney involvement | No | Obesity; Insulin resistance; Dermal abnormalities; EDL | No |
Age of liver biopsy | NA | 2.5y | 4.5y | NA | NA | NA | NA | NA | NA | NA | 5m | NA | 1y | 5m<Age<1y | NA | NA | 6.5m |
Light microscopy of liver | NA | S; FI; MI | S; FI; MI | NA | NA | NA | NA | NA | NA | NA | S | NA | S; FI | S; C; I | S; FI | NA | S; FI; MI |
Electron microscopy of liver | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | NA | Vesicles between the hepatocytes | NA | NA | NA | Lipid droplets in hepatocytes |
Mutations (NM_005276) | c.361-1G>C; Homo | R229Q+ a long deletion | Arg269Gln; Homo | c.361- 1G > C; Homo | Cys214Arg; Homo | Cys214Arg; Homo | c.220-2A>G + Ala274Thr | Q175a; Homo |
Reference | Basel-Vanagaite et al., 2012 | Joshi et al., 2014 | Dionisi-Vici et al., 2016 | Li et al., 2017 | This study |
Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis, and obesity. Several genetic defects for hypertriglyceridemia have been identified, including mutations in
APOA5 (MIM 606368) [
9],
LIPI (MIM 609252) [
10],
LPL (MIM 609708) [
11],
APOC2 (MIM 608083) [
12],
LIPC (MIM 151670) [
13],
USF1 (MIM 191523) [
14],
GPIHBP1 (MIM 612757) [
15], and
LMF1 (MIM 611761) [
16].
GPD1 disease is one of the important molecular etiologies of primary hypertriglyceridemia with onset in infancy [
3]. Basel-Vanagaite
et al. confirmed that mutation of
GPD1 in HepG2 cells causes increased triglyceride synthesis and secretion [
3]. However, the exact mechanism of hypertriglyceridemia in
GPD1 deficiency is unclear and remains to be further clarified. Notably, high triglyceride level is an independent risk factor for coronary artery disease and also associated with an increased risk of acute pancreatitis [
17‐
19]. The long term effects of hypertriglyceridemia on patients with HTGTI is unknown, and it is necessary to pay attention to these patients in their long-term follow up.
All the
GPD1 deficiency patients had fatty liver on ultrasound or other imaging examinations. Light microscopy undertaken in 6 of sixteen previous affected patients showed steatosis with varying degree of fibrosis. Joshi M
et al. proposed that fatty liver in
GPD1 disease may be due to acylation of excess DHAP [
5]. The detailed mechanisms are not clear and further research is needed to shed light on them. Fatty liver with hepatomegaly can be caused by a spectrum of inherited metabolic liver diseases, such as glycogen storage disease, lipidosis, lysosomal diseases, and citrin deficiency. Liver biopsy and genetic analysis are both useful for differential diagnosis of HTGTI and those diseases. However, the definite diagnosis of HTGTI depends on genetic testing.
The natural history of HTGTI is not clear yet. Although most patients presented with liver fibrosis in early infancy, all affected individuals had a good prognosis. At the time of their last evaluation, the levels of triglyceride and liver enzymes were improved in most patients. In addition, the oldest patient (aged 31 years) was doing well [
6]. Thus, liver transplantation is not recommended for HTGTI patients. Since triglyceride levels could be improved without specific therapy, we don’t recommend lipoprotein apheresis as routine therapy for these patients. But it could be an option for patients with severe hyperlipemia. We recommend to evaluate the growth and development and test liver function, total cholesterol, triglycerides, abdominal ultrasound, FibroScan and other abnormal index in the follow-up visit. In addition, it is necessary to pay attention to coronary artery disease and pancreatitis in their long-term follow up, which is associated with hypertriglyceridemia.
Previously, a total of 5 mutations in the GPD1 gene have been identified in 15 patients with HTGTI. In this study, we reported a novel disease-causing mutation c.523C>T, which is predicted to result in nonsense mediated mRNA decay. Among the 16 patients carrying biallelic mutations in GPD1, 15 patients showed a homozygous mutation, while only 1 patient was compound heterozygotes. The identified variants comprised 1 nonsense (c.523C>T), 3 missense (c.686G>A, c.806G>A, and c.640T>C), 1 splice site variant (c.361-1G>C), and 1 deletion mutation (28.7 kb > the deletion size > 1.85 kb).
In conclusion, we reported a Han Chinese HTGTI patient with mutation of GPD1, having hypertriglyceridemia, hepatomegaly, mildly elevated transaminases, and hepatic steatosis. GPD1 deficiency should also be considered in children and adolescents with hypertriglyceridemia and hepatic steatosis of unknown causes, and that the natural history of the condition is still unknown.